Synthesis, biological evaluation of 5-carbomethoxymethyl-7-hydroxy-2- pentylchromone, 5-carboethoxymethyl-4′,7-dihydroxyflavone and their analogues

Article abstract of DOI:10.1016/j.bmcl.2012.05.007

In this letter, we describe the first synthesis of two recently isolated flavones 5-carbomethoxymethyl-7-hydroxy-2-pentylchromone (3a), 5-carboethoxymethyl-4′,7-dihydroxyflavone (3b) and their derivatives (3c-t), evaluated for their antimicrobial, antioxi

Full text of DOI:10.1016/j.bmcl.2012.05.007

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4891–4895
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, biological evaluation of 5-carbomethoxymethyl-7-hydroxy-2-pent-
ylchromone, 5-carboethoxymethyl-40,7-dihydroxyflavone and their analogues
Ahmed Kamal a, , J. N. S. R. C. Murty a, A. Viswanath a, P. Sujitha b, C. Ganesh Kumar b
⇑
a Division of Organic Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India
b Chemical Biology Laboratory, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In this letter, we describe the first synthesis of two recently isolated flavones 5-carbomethoxymethyl-7-
hydroxy-2-pentylchromone (3a), 5-carboethoxymethyl-40,7-dihydroxyflavone (3b) and their derivatives
(3c–t), evaluated for their antimicrobial, antioxidant and anticancer activities. Most of the synthesized
compounds exhibited antimicrobial activity against the tested microbial strains and some of these com-
pounds were found to be more potent as compared to the standard drugs like neomycin and luteolin.
Interestingly, some of these synthesized compounds also showed moderate antioxidant property.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 11 March 2012
Revised 18 April 2012
Accepted 2 May 2012
Available online 23 May 2012
Keywords:
Antimicrobial agents
Antioxidant agents
Flavones
A number of reasons induce the emergence of antimicrobial
resistance among bacteria, but the common factors are the genetic
mutation or transfer in housekeeping structural or regulatory
genes.1 Structural modification of antimicrobial drugs to which
resistance has developed has proven to be an effective means of
extending the lifespan of antimicrobial agents such as the azoles,3
non-nucleoside reverse transcriptase inhibitors,4 quinolones.2 Bac-
terial infections are known to generate free radicals.5 The role of
free radicals and active oxygen (O2Åꢀ, H2O2, OHÅꢀ etc) is becoming
increasingly recognized in the pathogenesis of the many human
diseases, including cancer, neurodegenerative diseases, ageing
and atherosclerosis.6 Cancer on the other hand is one of the leading
causes of death worldwide and accounted for 7.9 million deaths
(around 13% of all deaths) in 2007, with an estimated 12 million
deaths in 2030.
Flavones are a class of flavonoids based on the backbone of 2-
phenylchromen-4-one (2-phenyl-1-benzopyran-4-one). Flavones
are well known for their antioxidant,7 antimicrobial,8 anticancer9
and several other pharmacological activities.10 Among them, the
naturally occurring chrysin (1)11 or luteolin (2)12 (Fig. 1), are poly-
hydroxylated compounds and their synthetic analogs have showed
considerable antimicrobial and antioxidant properties, which gen-
erated an interest to synthesize these type of molecules. Recently,
5-carbomethoxymethyl-7-hydroxy-2-pentylchromone (3a) and 5-
carboethoxymethyl-40,7-dihydroxyflavone (3b) were isolated from
the herb Selaginella moellendorffii Hieron and Rhizophora mucronata,
respectively, that exhibit antitumor activity against MCF7 and lung
cancer cell lines.13,14
As a part of our ongoing research program in the search for
potent molecules containing different heterocyclic scaffolds that
exhibit antimicrobial and anticancer activities,15 and based on
the interesting biological activities of polyhydroxylated flavones
as antimicrobial as well as antioxidants, we became interested to
synthesize the recently isolated flavones 3a, 3b and their deriva-
tives, evaluated for their antimicrobial, antioxidant and anticancer
activities. Further, all the flavones are synthetically new and the
synthesis of 3a and 3b has not yet been reported elsewhere.
The synthesis of 5-carbomethoxymethyl-7-hydroxy-2-pent-
ylchromone (3a), 5-carboethoxymethyl-40,7-dihydroxyflavone
(3b) and their derivatives (3c–t) were prepared in three to four
steps through methyl curvulinate (4) from dimethyl-3-oxoglutar-
ate as described in previous literature.16 From methyl curvulinate
(4), flavones were synthesized in two ways.
The compound 4 on treating with acid chloride (RCOCl/ArCOCl)
provided the diester 5. Later this diester (5) was treated with NaH
in THF undergoes Baker-Venkatraman rearrangement17 and gave
the compound 6 followed by reflux with HCl in acetic acid provides
the desired flavone (3a–s) as shown in Scheme 1.
The compound 4 on condensed with different substituted alde-
hydes in the presence of 5% aqueous sodium hydroxide provided
the different chalcone acid derivatives (7a–s). The oxidative cycli-
zation of the chalcone acids (7a–s) with ferric chloride in methanol
afforded the corresponding flavone acids 8a–s.18 By treating these
flavone acids with methanol or ethanol in the presence of catalytic
amount of conc. sulfuric acid gave their corresponding flavone
esters 3a–s (Scheme 2).
⇑
Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189.
E-mail address: ahmedkamal@iict.res.in (A. Kamal).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.007

4892
A. Kamal et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4891–4895
OH
OH
HO
O
O
HO
O
O
HO
O
O
OH
H3COOC
Ar
OH
3a
chrysin (1)
luteolin (2)
OH
HO
O
O
HO
O
O
H
HO
O
O
H3COOC
H3COOC
C2H5OOC
3b
3c-s
3t
Figure 1. Chemical structures of chrysin (1), luteolin (2), 5-carbomethoxymethyl-7-hydroxy-2-pentylchromone (3a), 5-carboethoxymethyl-40,7-dihydroxyflavone (3b), 5-
carbomethoxy methyl-7-hydroxy-2-arylchromones (3c–s) and methyl 2-(7-hydroxy-4-oxo-4H-chromen-5-yl)acetate (3t).
HO
OH
ROCO
OCOR
HO
OH
O
i
ii
R
COCH3
COCH3
O
H3COOC
H3COOC
H3COOC
4
6
5
iii
3a: R = n−pentyl
3c: R = 3',4',5'−trihydroxyphenyl
3d: R = 3',4'−dihydroxyphenyl
3e: R = 2',4'−dihydroxyphenyl
3f: R = 2',5'−dihydroxyphenyl
HO
O
R
3g: R = 4'−hydroxy−3'−methoxyphenyl
3h: R = 3'−hydroxy-4'−methoxyphenyl
O
3i:
R = 3,'5'−dimethoxyphenyl
R = 3,'4'−dimethoxyphenyl
R = 4'−methoxyphenyl
H3COOC
3j:
3a, 3c-s
3k:
3l:
R = 3,'4',5'−trimethoxyphenyl
R = 4'−methylphenyl
3m:
3n:
R = 2'−chloro−3'−methoxyphenyl
3o: R = 3'-fluoro-4'-chlorophenyl
3p: R = 4'-chlorophenyl
3q: R = 4'−aminophenyl
3r: R = 4'−nitrophenyl
3s: R = phenyl
Scheme 1. Reagents and conditions: (i) acid chloride (RCOCl/ArCOCl), dry pyridine, CH2Cl2, rt, 24 h (79%); (ii) NaH, dry THF, 24 h, reflux; (iii) Conc. HCl, CH3COOH, reflux, 6 h
(41%).
Most of the analogs have been prepared using method I (Baker
Venkatraman route). The method is facile and involves easy work-
up procedures but few analogs containing phenolic-OH, and halo
groups are obtained in poor yield through this method. In order
to obtain good yields of the analogs containing phenolic OH and
halo groups, method II is adopted (Chalcone route). Though meth-
od II involves high reaction times the yields of the desired products
are good compared to method I.
However, the antibacterial activity of all the compounds with few
exceptions showed moderate to good activity against the tested
bacterial strains.
All the compounds were examined for their in vitro antifungal
activity by well diffusion method19 against various pathogenic
Candida reference strains like Candida albicans (MTCC 3018), Can-
dida albicans (MTCC 1637), Candida glabrata (MTCC 3019), Candida
albicans (MTCC 3958), Candida albicans (MTCC 227), Candida albi-
cans (MTCC 7315), Candida albicans (MTCC 854), Candida albicans
(MTCC 183), Candida albicans (MTCC 3017), Candida albicans (MTCC
4748), Candida parapsilosis (MTCC 1744) and Issatchenkia orientalis
(MTCC 3020). These compounds were tested for Minimum Inhibi-
tory Concentration (MIC). The antifungal activities were compared
to the standard antifungal agent fluconazole. Among all the tested
compounds (3a–t), only compound 3o which contained the 30-flu-
oro and 40-chloro substitution on the B-ring showed good antifungal
activity against Candida albicans (MTCC 3958), Candida albicans
(MTCC 7315), Candida albicans (MTCC 854), Candida albicans (MTCC
4748) and Candida parapsilosis (MTCC 1744) strains with MIC rang-
Compound 4 was further treated with methylorthoformate and
perchloric acid to provide the desired compound 3t.
The synthesized compounds were examined for their in vitro
antibacterial activity by modified microtiter broth dilution meth-
od19 against a panel of various Gram-positive bacterial strains like
Bacillus subtilis (MTCC 121), Staphylococcus aureus (MTCC 2940),
Micrococus luteus (MTCC 2470) and Staphylococcus aureus (MTCC
96), as well as Gram-negative bacterial strains like Escherichia coli
(MTCC 739), Pseudomonas aeruginosa (MTCC 2453) and Klebsiella
planticola (MTCC 530). Among all the tested compounds, the com-
pounds 3i, 3j, 3k and 3l showed significant antibacterial activity
against all the tested bacterial strains although the remaining com-
pounds showed moderate to good antibacterial activity with MIC
ing between 4 and 9 lg/mL. Fluconazole, a positive control in the
assay exhibited MIC values ranging between 16 and 64 lg/mL
of 4–9
lg/mL against one or two tested bacterial strains (Table 1).
against the tested Candida strains as shown in Table 2.

A. Kamal et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4891–4895
4893
Table 1
Antibacterial activity of compounds (3a–t)
Compound
Minimum inhibition concentration (MIC,
l
g/mL)a
S. ab
B. sb
S. mb
M. lb
K. p.c
E. cc
P. ac
d
d
d
d
d
d
d
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
9
—
9
9
—
—
18
37
18
—
—
18
18
—
18
75
—
18
9
—
—
9
—
—
—
—
4
—
—
—
—
—
—
—
9
—
—
9
—
—
9
9
9
—
—
—
9
—
18
18
—
9
18
—
37
—
—
9
—
9
—
—
—
—
—
9
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
—
—
9
d
d
d
37
18
18
4
18
9
d
d
d
d
—
9
18
4
9
9
—
18
9
9
d
d
d
d
37
—
—
d
d
d
d
9
9
4
—
—
—
4
18
18
4
37
18
9
18
9
18
d
d
d
d
d
d
9
—
—
—
—
—
—
—
d
d
d
75
18
d
d
d
d
—
9
37
—
—
37
d
d
d
d
d
3q
3r
3s
3t
—
—
—
—
——d
37
—
9
—
—
d
18
18
d
d
d
d
d
d
—
—
—
—
—
—
—
—
d
d
d
d
d
d
d
Neomycin
Luteolin
18
18
18
—
18
9
18
18
18
—
18
4
18
—
d
d
d
a
b
c
MIC values are mean of three determinations.
Gram-positive bacteria.
Gram-negative bacteria.
d
Not active at 80 lg/mL, B. s (Bacillus subtilis MTCC 121); S. m (Staphylococcus aureus MTCC 2940); M. l (Micrococcus luteus MTCC 2470); S. a (Staphylococcus aureus MTCC
96); E. C (Escherichia coli MTCC 739); P. a (Pseudomonas aeruginosa MTCC 2453); K. p (Klebsiella planticola MTCC 530).
HO
O
R
HO
O
O
R
HO
OH
O
R
HO
OH
i
iii
ii
COCH3
O
H3COOC
HOOC
HOOC
H3COOC
8a-s
4
3a, 3c-s
7a-s
iv
3a:
3c:
3d:
3e:
R = n−pentyl
v
R = 3',4',5'−trihydroxyphenyl
R = 3',4'−dihydroxyphenyl
R = 2',4'−dihydroxyphenyl
HO
O
O
R
3f: R = 2',5'−dihydroxyphenyl
3g: R = 4'−hydroxy−3'−methoxyphenyl
3h: R = 3'−hydroxy-4'−methoxyphenyl
3i: R = 3,'5'−dimethoxyphenyl
3j: R = 3,'4'−dimethoxyphenyl
3k: R = 4'−methoxyphenyl
R1OOC
3b R = 4'-hydroxyphenyl, R1 = CH2CH3
3t
3l: R = 3,'4',5'−trimethoxyphenyl
R = H, R1 = CH3
3m:
3n:
3o:
3p:
3q:
3r:
R = 4'−methylphenyl
R = 2'−chloro−3'−methoxyphenyl
R = 3'-fluoro-4'chlorophenyl
R = 4'-chlorophenyl
R = 4'−aminophenyl
R = 4'−nitrophenyl
3s: R = phenyl
Scheme 2. Reagents and conditions: (i) substituted aldehydes, methanol, 5% aq. NaOH, 24–48 h, rt (70–85%); (ii) FeCl3, MeOH, reflux, 8–12 h (80–85%); (iii) cat. conc. H2SO4,
methanol, reflux, 10–18 h (70–80%); (iv) CH(OCH3)3, methanol, HClO4, rt, 1 h (59%); (v) cat. conc. H2SO4, ethanol, reflux, 18 h (71%).
Flavones have been shown to act as scavengers of various oxi-
dizing species that is, superoxide anion, hydroxyl radical or peroxy
radicals. They may also act as quenchers of singlet oxygen. They do
not react specifically with a single species and so a number of dif-
ferent evaluation methods have been developed which makes
comparison among these various studies very difficult. All the syn-
thesized compounds (3a–t) were investigated for their in vitro
antioxidant potentials in different oxidizing systems viz. radical
scavenging activity by 1,1-diphenyl-2-picrylhydrazyl (DPPH)
reduction,20 superoxide radical scavenging activity,21 inhibition
of lipid peroxidation22 and hemolysis in erythrocyte membrane
stabilization23 at a single concentration of 16
lg/mL. Ascorbic acid
and luteolin were employed as standards in these assays.
The antioxidant activity of all the compounds 3a–t except 3b,
3c, 3d, 3e and 3o were found to be unstable and the reaction
was reversible after 48 h. The compounds 3b, 3c, 3d, 3e and 3o
showed moderate activity against all the antioxidant methods.
However, the compounds 3b, 3o showed no activity for lipid per-
oxidation inhibition and erythrocyte hemolysis inhibition. Further-
more, substitution in the aromatic ring system with o-dihydroxy
sharply enhanced the antioxidant potency. This is why compound
3d showed prominent antioxidant activity in all the antioxidant

4894
A. Kamal et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4891–4895
o-dihalo (30-floro-40-chloro) groups are the key requirement for
Table 2
Antifungal activity of compound 3o
the antioxidant property of the synthesized flavones. Further,
among all the tested compounds, only compound 3d showed
excellent antioxidant activity with all the tested antioxidant
methods. These results provide an insight for necessary structural
modifications thereby leading to compounds with favorable phar-
macological properties. Moreover these compounds (3g, 3l, 3m, 3c,
3h, 3p, 3o and 3d) may be considered molecules as potential
antimicrobial and antioxidant agents.
Strains
Minimum inhibitory concentration (MIC, lg/mL)
Compound 3o
Flucanazolea
C.a1
C.a2
C.a3
C.a4
C.a5
C.a6
C.a7
C.a8
C.a9
C.a10
C.a11
I.o
4
4
9
9
9
9
—
—
—
—
64
32
32
32
16
16
32
64
32
32
64
128
b
b
Acknowledgements
b
b
The authors J.N.S.R.C.M., A.V and P.S. are thankful to CSIR, New
Delhi, for the award of research fellowships.
b
—
—
b
a
Positive control. C.a1 (Candida albicans MTCC 3958), C.a2 (Candida albicans
References and notes
MTCC 4748), C.a3 (Candida albicans MTCC 7315), C.a4 (Candida albicans MTCC 854),
C.a5 (Candida parapsilosis MTCC 1744), C.a6 (Candida parapsilosis MTCC 3018),
C.a7(Candida albicans MTCC 1637), C.a8 (Candida glabrata MTCC 3019), C.a9 (Can-
dida albicans MTCC 227), C.a10 (Candida albicans MTCC 183), C.a11 (Candida albicans
MTCC 3017), I.o (Issatchenkia orientalis MTCC 3020)
1. Courvalin, P.; Cuot, P. T. Clin. Infect. Dis. 2001, 33, S138.
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b
Not active.
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Matlawska, I.; Pilewski, N. A. JANA 2004, 7, 24.
Table 3
Antioxidant activities of the synthesized flavones
Compound
EC50
SASA
(
l
g/mL)a
LPI
DRSA
EHI
3b
3c
3d
3e
3f
3o
71.11
55.08
49.99
60.00
119.11
61.66
40.28
44.18
77.71
50.09
44.08
60.90
106.22
60.92
21.01
31.01
171.54
151.10
139.76
127.98
9. Leu, Y. I.; Ho, D. K.; Cassady, J. M.; Cook, V. M.; Barid, W. M. J. Nat. Prod. 1992, 55,
357.
156.21
142.00
c
c
10. (a) Wu, E. S. C.; Loch, J. T.; Toder, B. H.; Borrelli, A. R.; Gawlak, D.; Radov, L. A.;
Gensmantel, N. P. J. Med. Chem. 1992, 35, 3519; (b) Wolfman, C.; Viola, H.;
Marder, M.; Wasowski, C.; Ardenghi, P.; Izquoerdo, I.; Paladini, A. C.; Medina, J.
H. Eur. J. Pharmacol. 1996, 318, 23; (c) Akama, T.; Ishida, H.; Kimura, U.; Gomi,
K.; Saito, H.; Fuse, E.; Kasai, M. J. Med. Chem. 1997, 40, 1894; (d) Gee, J. M.;
Johnson, I. T. Curr. Med. Chem. 2001, 8, 1245.
—
—
221.12
209.56
c
c
—
—
Ascorbic acidb
Luteolinb
139.97
134.1
119.81
122.00
11. Babu, S. K.; Babu, H. T.; Srinivas, P. V.; Kishore, K. H.; Murthy, U. S. N.; Rao, J. M.
Bioorg. Med. Chem. Lett. 2006, 16, 221.
12. López-Lázaro, M. Mini-Rev. Med. Chem. 2009, 9, 31.
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Proksch, P. J. Nat. Prod. 2009, 72, 662.
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Lu, L. F.; Wang, Q. Fitoterapia 2010, 81, 253.
a
b
c
EC50 values are means of three experiments.
Positive control.
Not active; DRSA (= DPPH radical scavenging activity); SASA (= Superoxide
anion scavenging activity); LPI (= Lipid peroxidation inhibition); EHI (= Erythrocyte
hemolysis inhibition) (remaining compounds are not active).
15. (a) Kamal, A.; Reddy, B. S. P.; Thurston, D. E. Bioorg. Med. Chem. Lett. 1993, 3,
743; (b) Kamal, A.; Khan, M. N. A.; Reddy, K. S.; Rohini, K.; Sastry, G. N.; Sateesh,
B.; Sridhar, B. Bioorg. Med. Chem. Lett. 2007, 17, 5400.
methods. The compound 3d showed prominent antioxidant activ-
ity in all the antioxidant methods. Interestingly, the active com-
pounds having hydroxyl groups and halo groups like F and Cl
only exhibited antioxidant activity, therefore, it is considered that
these groups play a significant role in the antioxidant mechanisms
(Table 3).
Some of the synthesized compounds (3g, 3h, 3i, 3q, 3m, 3k and
3j) were screened for 60 cancer cell lines by National Cancer Insti-
tute (NCI), and no appreciable activity was observed for these
compounds.
Most of these synthesized flavones showed significant antibac-
terial activity with IC50 values varying in the range of 4–18 lg/mL.
Among all the tested compounds, the compounds 3g, 3l and 3m
exhibited excellent antibacterial activity against Bacillus subtilis
MTCC 121, Micrococcus luteus MTCC 2470 and Escherichia coli MTCC
16. (a) Takeuchi, N.; Sasaki, Y.; Kosugi, Y.; Tobinaga, S. Chem. Pharm. Bull. 1989, 37,
2012; (b) Chinose, K. I.; Bizuka, Y. E.; Ankawa, U. S. Chem. Pharm. Bull. 2001, 49,
192; (c) Elzner, S.; Schmidt, D.; Schollmeyer, D.; Erkel, G.; Anke, T.; Kleinert, H.;
Fçrstermann, U.; Kunz, H. ChemMedChem 2008, 3, 924; General experimental
procedure for the synthesis of methyl or ethyl ester of 5-carboxymethyl-7-hydroxy
chromones. Method I: The compound 4 (224 mg, 1.0 mmol) dissolved in dry
pyridine (10 mL) and add freshly prepared or distilled acid chloride (RCOCl/
ArCOCl) (2.1 mmol) under cooling in an ice-bath to keep the reaction
temperature at about 20 °C. The mixture was stirred for 24 h at room
temperature. Work up by the usual procedure gave a crude ester, which was
dried, dissolved in dry THF (20 mL) and added slowly at 0 °C under argon
atmosphere to a suspension of sodium hydride (95% pure, 120 mg, 5.0 mmol)
in dry THF (20 mL). The mixture was refluxed for 24 h then poured into cold
acetic acid (20 mL) with caution and extracted with ethyl acetate (3 ꢁ 30 mL).
The residue from the combined ethyl acetate extracts was dissolved in acetic
acid (10 mL) and conc. HCl (2 mL) then refluxed for 6 h. The mixture was
poured into water, and extracted with ethyl acetate. Subsequent drying over
Na2SO4 and evaporation yielded (3a–s), which was crystallized in methanol to
give pure compound (34–72% yields over 3 steps). Method II: The compound 4
(224 mg, 1.0 mmol) dissolved in methanol (20 mL) and add substituted
aldehydes (1.1 mmol) and 50% NaOH (5 mL). The reaction mass was refluxed
for 12 h. Workup by the usual procedure gave a crude chalcone acid, which was
dried, dissolved in methanol (20 mL) and add excess FeCl3 (about 300 mg) and
refluxed for 12 h. Then ice-cold water was added to the reaction mixture,
extracted with ethyl acetate (4 ꢁ 20 mL) and dried over Na2SO4. The residue
from the combined ethyl acetate extracts was dissolved in methanol/ethanol
and catalytic amount of conc. H2SO4 (0.2 mL) was added, refluxed for 12 h. The
product worked up as usual and subjected to silica gel column chromatography
to get the pure compound (24–44% yield over 3 steps). 5-Carbomethoxymethyl-
739, respectively, with MIC of 4 lg/mL. Among all the compounds,
only compound 3o showed antifungal activity against most of
tested Candida strains with MIC values ranging between 4 and
9
lg/mL.
The compound 3a and 3t were totally inactive towards four
antioxidant properties, while 3h, 3j, 3i, and 3l which carries a p-
methoxy group, was weakly active. Thus, it appears that flavones
require the presence of a 40-hydroxy group in order to successfully
inhibit lipid peroxidation as well as other antioxidant properties.
Our results also indicate that the presence of an o-dihydroxy and
7-hydroxychromone (3t): To
a solution of 4 (224 mg, 1.0 mmol) in
trimethylorthoformate (10 mL), add perchloric acid (60%, 0.80 mL, 5.0 mmol)

A. Kamal et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4891–4895
4895
at 0 °C. The stirring was continued for 12 h at room temperature. After
completion of the reaction as indicated by TLC, the reaction mixture was
diluted with water and extracted with ethyl acetate. The residue obtained after
concentration was purified by column chromatography to gave the compound
3t as a white solid (154 mg, 66% yield). Mp 78–80 °C; 1H NMR (DMSO-d6,
300 MHz): d ppm 11.10–10.28 (br s, 1H), 8.00 (1H, d, J = 5.5 Hz), 6.75 (s, 1H),
6.69 (s, 1H); 6.06 (1H, d, J = 6.6 Hz). 4.05 (s, 2H), 3.56 (s, 3H); 13C NMR (DMSO-
d6, 75 MHz): d ppm 178.1, 161.2, 159.7, 154.9, 143.0, 117, 116, 113.3, 101.0,
59.0, 40.4; MS (ESI): m/z 235 (M+H)+; HRMS (ESI m/z) for C12H10O5 calcd
235.0601, found 235.0605 (M+H)+. 5-Carbomethoxymethyl-7-hydroxy-2-
pentylchromone (3a): The compound 3a was prepared according to the
general procedure I. Yield 66%, mp 49–51 °C. 1H and 13C spectra are in
agreement with those reported in literature.13; MS (ESI): m/z 305 (M+H)+;
3.90 (s, 3H), 3.86 (s, 3H), 3.74 (s, 3H); 13C NMR (DMSO-d6, 75 MHz): d ppm
177.4, 160.9, 160.5, 158.2, 151.6, 149.3, 138.0, 122.7, 120.1, 118.2, 113.8, 112.0,
109.5, 106.7, 102.1, 59.0, 57.0, 54.3, 40.6; MS (ESI): m/z 371 (M+H)+; HRMS (ESI
m/z) for
C
20H18O7 calcd 371.1125, found 371.1129 (M+H)+. 5-
Carbomethoxymethyl-7-hydroxy-30,50-dimethoxyflavone (3k): The compound
3k was prepared according to the general procedure II. Yield 30%, Mp. 100–
103 °C. 1H NMR (DMSO-d6, 300 MHz): d ppm 7.29 (d, 1H, J = 2.0 Hz), 7.20 (s,
1H), 6.66–6.67 (d, 2H, J = 2.2 Hz), 6.60 (d, 1H, J = 2.0 Hz), 6.45–6.46 (d, 1H,
J = 2.2 Hz), 4.05 (s, 2H), 3.87 (s, 6H), 3.74 (s, 3H); 13C NMR (DMSO-d6, 75 MHz):
d ppm 177.5, 161.2, 161.1, 160.1, 158.4, 138.1, 132.5, 118.4, 114.5, 108.6, 104.6,
103.2, 102.3, 59.7, 55.3, 42.3; MS (ESI): m/z 371 (M+H)+; HRMS (ESI m/z)
for C20H18O7 calcd 371.1125, found 371.1128 (M+H)+. 5-carbomethoxymethyl-
7-hydroxy-30,40,50-trimethoxyflavone (3l): The compound 3l was prepared
according to the general procedure I. Yield 70–74%, mp 93–95 °C. 1H NMR
(DMSO-d6, 300 MHz): d ppm 6.86 (s, 2H), 6.37 (s, 1H), 6.38 (s, 1H), 5.36–5.40
(d, 1H, J = 9.7 Hz), 3.90 (s, 2H), 3.88 (s, 3H), 3.79 (s, 6H), 3.67 (s, 3H); 13C NMR
(DMSO-d6, 75 MHz): d ppm 177.9, 161.2, 160.3, 158.8, 153.7, 140.6, 138.2,
126.3, 118.6, 115.5, 106.6, 105.0, 102.2, 59.2, 57.3, 53.1, 39.1; MS (ESI): m/z 401
(M+H)+; HRMS (ESI m/z) for C21H20O8 calcd 401.1231, found 401.1236 (M+H)+.
5-Carbomethoxymethyl-7-hydroxy-40-methylflavone (3m): The compound 3m
was prepared according to the general procedure II. Yield 34%, Mp. 68–71 °C.
1H NMR (DMSO-d6, 300 MHz): d ppm 7.87–7.92 (d, 2H, J = 8.2 Hz), 7.34–7.38
(d, 2H, J = 8.0 Hz), 6.85 (d, 1H, J = 2.2 Hz), 6.68 (d, 1H, J = 1.8 Hz), 6.65 (s, 1H),
4.01 (s, 2H), 3.86 (s, 3H), 2.36 (s, 3H); 13C NMR (DMSO-d6, 75 MHz): v ppm
181.4, 161.5, 160.8, 158.8, 143.2, 138.1, 129.6, 127.9, 126.3, 118.4, 115, 107.1,
102.1, 55.4, 40.2, 19.9 ; MS (ESI): m/z 325 (M+H)+; HRMS (ESI m/z) for C19H16O5
calcd 325.1071, found 325.1076 (M+H)+. 5-Carbomethoxymethyl-7-hydroxy-20-
chloro-30-methoxyflavone (3n): The compound 3n was prepared according vto
the general procedure II. Yield 81%. Mp. 157–158 °C; 1H NMR (DMSO-d6,
300MHz): d ppm 11.35–10.87 (br s, 1H); 7.13 (t, 1H, J = 7.7 Hz); 6.96–6.95 (d,
1H, J = 7.7 Hz), 6.90–6.88 (d, 1H, J = 7.7 Hz), 6.40 (s, 1H), 6.29 (1H, s), 3.86 (s,
2H), 3.79 (s, 3H), 3.59 (s, 3H); MS (ESI): m/z 375 (M+1)+. 5-
Carbomethoxymethyl-7-hydroxy-30-floro-40-chloroflavone (3o): The compound
3o was prepared according to the general procedure I. Yield 55% Mp. 133–
134 °C; 1H NMR (300 MHz, DMSO-d6): d ppm 8.38 (d, 1H, J = 2.1 Hz), 7.97 (dd,
1H, J = 2.1, 9.2 Hz), 7.67 (d, 1H, J = 9.2 Hz), 7.01 (s, 1H), 6.86 (d, 1H, J = 2.2 Hz),
6.70 (d, 1H, J = 2.2 Hz), 3.84 (s, 2H), 3.76 (s, 3H); MS (ESI): m/z 363 (M+1)+. 5-
Carbomethoxymethyl-7-hydroxy-40-chloroflavone (3p): The compound 3p was
prepared according d to the general procedure II. Yield 39%, Mp. 93–95 °C. 1H
NMR (DMSO-d6, 300 MHz): d ppm 8.02–8.06 (d, 2H, J = 8.4 Hz), 7.59–7.63 (d,
2H, J = 8.8 Hz), 6.86 (d, 1H, J = 2.2 Hz), 6.75 (s, 1H), 6.70 (s, 1H), 3.92 (s, 2H),
3.81 (s, 3H); 13C NMR (DMSO-d6, 75 MHz): d ppm 198.3, 160.4, 160.1, 158. d 8,
138.9, 138.2, 129.4, 129.2, 127.7, 118.7, 115.1, 108.1, 102.2, 55.4, 40.7; MS
(ESI): m/z 345 (M+H)+; HRMS (ESI m/z) for C18H13ClO5 calcd 345.0524, found
345.0531 (M+H)+. 5-Carbomethoxymethyl-7-hydroxy-40-aminoflavone (3q): The
compound 3q was prepared according to the general procedure II. Yield 30%,
Mp. 164–166 °C. 1H NMR (DMSO-d6, 300 MHz): d ppm 7.72 (d, 2H, J = 8.7 Hz),
6.89 (d, 1H, J = 2.2 Hz), 6.75 (d, 2H, J = 8.7 Hz), 6.65 (d, 1H, J = 2.2 Hz), 6.53 (s,
1H), 6.04 (br s, 2H), 4.00 (s, 2H), 3.76 (s, 3H); 13C NMR (DMSO-d6, 75 MHz): d
ppm 179.9, 164.5, 161.7, 157.8, 153.5, 106.3, 133.7, 128.1, 118.4, 116.1, 101.9,
113.6, 111.2, 59.1, 41.6; MS (ESI): m/z 326 (M+H)+; HRMS (ESI m/z) for
HRMS (ESI m/z) for
C
18H22O5 calcd 305.1384, found 305.1391 (M+H)+.5-
Carbomethoxyethyl-7,40-dihydroxyflavone (3b): The compound 3b was prepared
according to the general procedure II. Yield 34%, mp 128–130 °C. 1H and 13C
spectra are in agreement with those reported in literature.14; MS (ESI): m/z 341
(M+H)+; HRMS (ESI m/z) for C19H16O6 calcd 341.1020, found 341.1027 (M+H)+.
5-Carbomethoxymethyl-7,30,40,50-tetrahydroxyflavone (3c): The compound 3c
was prepared according to the general procedure II. Yield 25%, mp 168–170 °C.
1H NMR (DMSO-d6, 300 MHz): d ppm 7.14 (s, 2H), 6.94 (d, 1H, J = 2.3 Hz), 6.89
(d, 1H, J = 2.3 Hz), 6.68 (s, 1H), 3.86 (s, 2H), 3.72 (s, 3H); 13C NMR (DMSO-d6,
75 MHz): d ppm 176.4, 160.9, 159.9, 157.3, 145.7, 145.1, 137.1, 116.8, 113.4,
105.6, 104.4, 104.2, 100.1, 57.9, 38.9; MS (ESI): m/z 359 (M+H)+; HRMS (ESI m/
z) for
C
18H14O8 calcd 359.0761, found 359.0756 (M+H)+. 5-
Carbomethoxymethyl-7,30,40-trihydroxyflavone (3d): The compound 3d was
prepared according to the general procedure II. Yield 25%, mp 170–172 °C.
1H NMR (DMSO-d6, 300 MHz): d ppm 8.24 (d, 1H, J = 2.0 Hz), 8.15 (dd, 1H,
J = 2.0, 8.0 Hz), 7.70 (d, 1H, J = 8.0 Hz), 6.74 (d, 1H, J = 2.0 Hz), 6.57 (d, 1H,
J = 2.0 Hz), 6.12 (s, 1H), 4.02 (s, 2H), 3.62 (s, 3H); 13C NMR (DMSO-d6, 75 MHz):
d ppm 176.6, 164.5, 160.1, 158.4, 151.3, 146.7, 138.0, 119.6, 119.0, 118.7, 116.1,
112.9, 112.3, 104.7, 102.3, 57.0, 41.6; MS (ESI): m/z 343 (M+H)+; HRMS (ESI m/
z) for
C
12H10O5 calcd 343.0812, found 343.0819 (M+H)+. 5-
Carbomethoxymethyl-7,20,40-trihydroxyflavone (3e): The compound 3e was
prepared according to the general procedure II. Yield 26%, mp 176–178 °C.
1H NMR (DMSO-d6, 300 MHz): d ppm 7.95 (d, 1H, J = 8.8 Hz), 7.15 (s, 1H), 6.98
(d, 1H, J = 2.1 Hz), 6.69 (d, 1H, J = 2.1 Hz), 6.57 (d, 1H, J = 2.3 Hz), 6.53–6.51 (m,
1H), 3.86 (s, 2H), 3.66 (s, 3H); 13C NMR (DMSO-d6, 75 MHz): d ppm 177.5,
160.8, 158.9, 158.5, 150.2, 149.8, 138.2, 117.5, 119.5, 118.4, 118.1, 113.8, 112.1,
105.5, 101.8, 58.0, 40.9; MS (ESI): m/z 343 (M+H)+; HRMS (ESI m/z) for
C
12H10O5 calcd 343.0812, found 343.0818 (M+H)+. 5-Carbomethoxymethyl-
7,20,50-trihydroxyflavone (3f): The compound 3f was prepared according to the
general procedure II. Yield 38%, mp 93–95 °C. 1H NMR (DMSO-d6, 300 MHz): d
ppm 7.38 (d, 1H, J = 2.9 Hz), 7.10 (s, 1H), 6.93–6.96 (m, 2H), 6.90 (dd, 1H, J = 2.9,
8.7 Hz), 6.71 (d, 1H, J = 2.1 Hz), 3.96 (s, 2H), 3.76 (s, 3H); 13C NMR (DMSO-d6,
75 MHz): d ppm 177.5, 160.8, 158.9, 158.5, 150.2, 149.8, 138.2, 119.5, 118.4,
118.1, 117.5, 114.5, 113.8, 112.1, 101.8, 59.7, 40.0; MS (ESI): m/z 343 (M+H)+;
HRMS (ESI m/z) for C18H14O7 calcd 343.0812, found 343.0818 (M+H)+. 5-
Carbomethoxymethyl-7,40-dihydroxy-30-methoxylflavone (3g): The compound 3g
was prepared according to the general procedure II. Yield 24%, Mp. 102–104 °C.
1H NMR (DMSO-d6, 300 MHz): d ppm 7.60 (dd, 1H, J = 2.0, 8.9 Hz), 7.53 (d, 1H,
J = 2.1 Hz), 6.99 (d, 1H, J = 8.5 Hz), 6.86 (s, 1H), 7.33 (d, 1H, J = 2.0 Hz), 6.65 (d,
1H, J = 2.0 Hz), 4.06 (s, 2H), 3.60 (s, 3H); 13C NMR (DMSO-d6, 75 MHz): d ppm
172.1, 164.8, 156.6, 151.1, 148.0, 145.7, 137.8, 130.2, 119.8, 116.9, 115.3, 113.3,
109.7, 104.2, 100.4, 58.0, 55.0, 42.0; MS (ESI): m/z 357 (M+H)+; HRMS (ESI m/z)
for C19H16O7 calcd 357.0969, found 357.0974 (M+H)+. 5-Carbomethoxymethyl-
7,30-dihydroxy-40-methoxylflavone (3h): The compound 3h was prepared
according to the general procedure II. Yield 29%, Mp. 72–74 °C. 1H NMR
C
18H15NO5 calcd 326.1023, found 326.1028 (M+H)+. 5-Carbomethoxymethyl-7-
hydroxy-40-nitrolflavone (3r): The compound 3r was prepared according to the
general procedure II. Yield 42%, Mp. 100–102 °C °C. 1H NMR (DMSO-d6,
300 MHz): d ppm 8.38 (d, 2H, J = 8.0 Hz), 8.01 (d, 2H, J = 8.0 Hz), 6.85 (d, 1H,
J = 1.6 Hz), 6.75 (s, 1H), 6.63 (d, 1H, J = 1.6 Hz), 3.99 (s, 2H), 3.79 (s, 3H); 13C
NMR (DMSO-d6, 75 MHz): d ppm 198.0, 161.4, 158.9, 158.7, 150.0, 137.7, 136.7,
127.2, 124.2, 118.9, 115.2, 110.2, 102.2, 56.0, 43.1; MS (ESI): m/z 356 (M+H)+;
HRMS (ESI m/z) for C18H13NO7 calcd 356.0765, found 356.0770 (M+H)+. 5-
Carbomethoxymethyl-7-hydroxyflavone (3s): The compound 3s was prepared
according to the general procedure II. Yield 40%, mp 102–104 °C 1H NMR
(DMSO-d6, 300 MHz): d ppm 7.92 (m, 2H), 7.51–7.54 (m, 3H), 6.84 (d, 1H,
J = 2.2 Hz), 6.69 (s, 1H), 6.60 (s, 1H), 3.96 (s, 2H), 3.87 (s, 3H); 13C NMR (DMSO-
d6, 75 MHz): d ppm 197.8, 160.9, 160.4, 159.3, 138.1, 132.7, 130.5, 129.4, 126.5,
118.5, 114.6, 108.1, 102.1, 55.4, 40.2; MS (ESI): m/z 311 (M+H)+; HRMS (ESI m/
z) for C18H14O5 calcd 311.0914, found 311.0919 (M+H)+.
(DMSO-d6, 300 MHz):
d ppm 7.51 (dd, 1H, J = 2.0, 8.9 Hz), 7.45 (d, 1H,
J = 2.1 Hz), 7.12 (d, 1H, J = 8.5 Hz), 6.93 (d, 1H, J = 2.0 Hz), 6.70 (d, 1H,
J = 2.0 Hz), 6.67 (s, 1H), 4.02 (s, 2H), 3.81 (s, 3H); 13C NMR (DMSO-d6,
75 MHz): d ppm 176.6, 160.4, 159.3, 157.3, 149.4, 145.4, 137, 121, 117.6, 116.7,
113.2, 111.2, 110.8, 104.7, 100.2, 57.1, 54.0, 39.0; MS (ESI): m/z 357 (M+H)+;
HRMS (ESI m/z) for C19H16O7 calcd 357.0969, found 357.0964 (M+H)+. 5-
Carbomethoxymethyl-7-hydroxy-40-methoxyflavone (3i): The compound 3i was
prepared according to the general procedure I. Yield 34%, Mp. 85–86 °C. 1H
NMR (DMSO-d6, 300 MHz): d ppm 7.76 (d, 1H, J = 2.3 Hz), 7.37–7.40 (d, 2H,
J = 8.7 Hz), 7.10 (d, 1H, J = 2.3 Hz), 6.92–6.94 (d, 2H, J = 8.7 Hz), 6.70 (s, 1H),
4.00 (s, 2H), 3.89 (s, 3H), 3.81 (s, 3H); 13C NMR (DMSO-d6, 75 MHz): d ppm
178.2, 162.9, 160.9, 160.5, 158.2, 138.0, 128.4, 122.6, 118.2, 114.8, 114.1, 106.4,
102.0, 58.0, 56.1, 41.1; MS (ESI): m/z 341 (M+H)+; HRMS (ESI m/z) for C19H16O6
calcd 341.1020, found 341.1029 (M+H)+. 5-Carbomethoxymethyl-7-hydroxy-
30,40-dimethoxyflavone (3j): The compound 3j was prepared according to the
general procedure II. Yield 28%, Mp. 106–108 °C. 1H NMR (DMSO-d6, 300 MHz):
d ppm 7.56 (d, 1H, J = 2.1 Hz), 7.25 (d, 1H, J = 2.1 Hz), 7.21 (dd, 1H, J = 2.1,
8.2 Hz), 7.12 (d, 1H, J = 2.2 Hz), 6.76 (d, 1H, J = 2.2 Hz), 6.63 (s, 1H), 4.01 (s, 2H),
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